3 : 3′-Diamidinocarbanilide: a New Drug Active against Babesial Infections

Ashley, J. N.; Berg, S. S.; Lucas, J.M.S.

doi:10.1038/185461a0

Cited by 20 publications

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“… 19 ). Amicarbalide is a benzamidine derivative that was used in veterinary medicine as an antiprotozoal drug against babesiosis, theileriosis and anaplasmosis 20 21 . Slow parasite clearance rates, high relapse frequencies, poor oral bioavailability, undesirable mutagenic and toxic side effects, and manufacturing safety issues were the reasons why this drug is no longer in use 21 22 .…”

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confidence: 99%

SC83288 is a clinical development candidate for the treatment of severe malaria

et al. 2017

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Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca2+ transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.

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SC83288 is a clinical development candidate for the treatment of severe malaria

et al. 2017

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“…Pentamidine (lomidine; 4,4'diamidino-1, 5-diphenoxypentane) is used quite widely, especially in North Africa, for babesiosis in all animals. Phenamidine (4, 4'-diamidinodiphenyl ether) Berg and Lucas (1960). Preliminary studies indicate that it is effective against babesiosis in cattle (Beveridge, Thwaite and Shepherd, 1960;Lucas, 1960 Artificial premunization of young animals has been practiced with a good deal of success, especially in North Africa (Sergent et al , 1945).…”

Section: Pathogenesismentioning

confidence: 99%

Protozoan parasites of domestic animals and of man

Levine¹

1961

515

493

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A disease which is common to man and lower animals is known as a zoo)iosis. Zoonoses were redefined in 1958 by the Joint WHO FAO Expert Committee on Zoonoses as "those diseases and infections which are naturally transmitted between vertebrate animals and man" (World Health Organization, 1959). Less than 20 years ago it was said that there were 50 zoonoses, but in the above report the World Health Organization listed more in connection with vector-borne diseases, altho it need not be restricted to them. epidemiology, taxonomy, evolution, etc.(see ). A dei)ie is a natural population within a species. It lies more or less below the subspecies level, but it is not a formal taxon and is not given a Latin name. There are different types of deme. Nosodemes differ in their clinical manifestations. One example is Leishmania donovani, which has five nosodemes, Indian, Mediterranean, Sudanese, Chinese and South American, which produce different types of disease. Serodemes differ serologically. These are best known among the bacteria and viruses, but also occur among the animal parasites. Tritrichonionas foetus, for example, has several serological types or serodemes. were markedly resistant to infection with Ostertagia circunicincta. while Rambouillets were less so and Southdowns, Shropshires and Hampshires were least resistant.Certain individuals among the more susceptible breeds, however, were just as resistant as the Romneys. Whitlock(1958) has studied genetic resistance to trichostrongylidosis in sheep in some detail.The nutritional status of the host may affect its resistance. Poorly nourished animals are usually more susceptible to infection and suffer more severely from its effects.Protein depletion or protein starvation is particularly important. Lack of specific vitamins and minerals generally decreases resistance, but there are cases in which lack of a certain vitamin which the parasite requires may affect the parasite adversely. Thus, Becker and Smith (1942) found that when calcium pantothenate was added to a ration containing restricted vitamins B,, Bg and pantothenate, the number of oocysts produced hy Einteria nieschulzi infections in the rat was increased.

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“…The toxic reactions of amicarbalide so far reported include local swelling at the injection site and mild ataxia in some animals (Ashley, Berg & Lucas, 1960;Beveridge, Thwaite & Shepherd, 1960).…”

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Some pharmacodynamic effects of the babesicidal agents quinuronium and amicarbalide

Eyre¹

1967

Journal of Pharmacy and Pharmacology

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The intravenous injection of a therapeutic dose of quinuronium methylsulphate (1 mg/kg) causes a fall in blood pressure in sheep, which is partly prevented by mepyramine and abolished by atropine. Larger doses of quinuronium cause more marked hypotension and inhibition of respiratory movement, which are not affected by atropine. Quinuronium strongly increases the amplitude of contraction of the isolated rabbit heart. This effect is not antagonized by atropine or mepyramine. Contractions of plain muscle in the guinea-pig and sheep, and hypersecretion of gastric acid in the rat and of saliva in the sheep were all produced by quinuronium. The responses to acetylcholine were potentiated by quinuronium, an effect which was abolished by atropine. Amicarbalide isethionate by comparison was weakly active. The drug causes no change in blood pressure, smooth muscle contraction or salivary secretion, but stimulates gastric secretion and partially inhibits the actions of acetylcholine in these preparations.

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3 : 3′-Diamidinocarbanilide: a New Drug Active against Babesial Infections

Cited by 20 publications

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SC83288 is a clinical development candidate for the treatment of severe malaria

SC83288 is a clinical development candidate for the treatment of severe malaria

Protozoan parasites of domestic animals and of man

Some pharmacodynamic effects of the babesicidal agents quinuronium and amicarbalide

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